Product Pipeline
About Hepatitis B
and Hepatitis C
Hepatitis B
Therapeutic Program
Hepatitis C
Therapeutic Program
DNA Delivery/
Manufacturing Technology
Clinicians who treat chronically infected HBV patients cite the following key unmet clinical needs as areas where they are looking for improvements in HBV therapeutics:
  • Improve patient response rates to therapy
  • Prevent drug resistance observed with conventional anti-viral therapy
  • Improve patient compliance with therapeutic regimens
  • Limit adverse side effects of drugs
Nucleonics believes that its eiRNA technology offers as unique opportunity to address all of the unmet clinical needs for HBV noted above. Accordingly, Nucleonics' most advanced drug candidate, NUC B1000, is specifically designed to be:
  • Effective against all HBV genotypes worldwide, including drug resistant strains
  • Resistant to viral escape mutants by virtue of its multi-target design
  • Capable of down-regulating multiple HBV antigens as well as inhibiting viral replication
  • Compatible with existing HBV therapies
The Company's HBV clinical candidate consists of a DNA plasmid vector formulated with a proprietary cationic-lipid delivery system. The active ingredient (i.e. the DNA vector) encodes four short hairpin RNA molecules ("shRNA"), each under the control of an RNA polymerase III promoter. Each of the 4 shRNA targets a different segment of the HBV genome (referred to as "sequitopes") and collectively they mediate the destruction of all RNA molecules produced by HBV within an infected cell through RNAi. Extensive characterization of this vector has shown that each shRNA contributes significantly to the potent anti-viral effect of the vector in HBV infected cells, such that effective inhibition of viral antigen production is obtained at sub-picomolar concentrations of vector in transfected cells in tissue culture. The figure below illustrates how the shRNA sequitopes map to the HBV genome and how the shRNA sequitopes are incorporated into Nucleonics' multi-sequitope HBV vector.
The diagram on the left illustrates how the sequitopes (A through D) selected for incorporation into Nucleonics HBV product NUC B100 map to the various genes in the HBV genome. These sequitopes target the various HBV genes in regions that are highly conserved among the various genotypes of HBV virus. By targeting the all genes in conserved regions, Nucleonics' product significantly limits the ability of HBV to mutate around the therapy and conveys coverage to all HBV genotypes. The right side shows how the four sequitopes from the left (A through D) are incorporated into the clinical DNA plasmid vector and the various features of the DNA plasmid vector.
Nucleonics believes that the multi-targeted shRNA design of NUC B1000 has the potential to treat chronic hepatitis B patients more profoundly and comprehensively than any other hepatitis B drug now available or currently in clinical development. The graphic below provides an overview of the HBV life-cycle and how NUC B1000 and other therapeutics impact that life-cycle.
The diagram depicts the full life cycle of HBV within an infected cell. The animation first depicts the impact of a conventional small molecule antiviral therapeutic that targets and disrupts just the polymerase which in turn disrupts viral particle formation and decreases viral load in the patient. The small molecule antiviral does not however impact other antigens which continue to be produced by the HBV virus inside an infected cell. The antigens not directly impacted by the small molecule antiviral continue to be produced which can promote the disease state of hepatitis. The final stage of the animation depicts the impact of NUC B1000 on an HBV infected cell. Because NUC B1000 targets all HBV antigens, the infected cell is cleared of all HBV antigens through the RNAi mechanism. The clearance of all HBV antigens by NUC B1000 is expected to provide an enhanced therapeutic effect in comparison to traditional small molecule antiviral that simply lower HBV viral load in a patient. (right click to view animation)
Other hepatitis anti-viral agents are designed to inhibit only a single gene within the HBV genome, the polymerase enzyme of the virus, and thereby disrupt viral replication within infected liver cells. Unfortunately, these anti-viral drugs are only partially effective, for two major reasons.
  • First, a large component of chronic hepatitis disease is a function not of viral replication, per se, but of viral antigen synthesis occurring as the result of ongoing viral RNA synthesis and expression. NUC B1000's primary mode of action is to directly destroy all viral RNAs before they can be translated into viral antigens within an infected cell. Moreover, since the RNAs also encode the various viral proteins needed for viral replication, ultimately viral replication is also shut down by NUC B1000.
  • The second reason that polymerase inhibitors such as lamivudine are only partially effective is that a chronic hepatitis B patient treated with this drug will develop drug-resistant variants of the virus which in turn pose a currently untreatable threat to the patient. However, since NUC B1000 targets 4 distinct sequence elements of the HBV genome, there is an infinitessimally small probability that drug resistant variants can develop during the course of treatment with NUC B1000.
Nucleonics has developed its hepatitis B program with the input of a number of prominent clinical specialists in viral hepatitis disease, all of whom have stressed the urgent need for a new treatment modality that can overcome the drawbacks of traditionally-designed antiviral drugs. NUC B1000 is on track for the filing of an Investigational New Drug application with the FDA in December 2006, with the expectation that Phase I clinical trials will commence in Q1 2007.